A new study shows that numerous processes involved in melanoma metastasis, which until now were believed to be independent of each other, have a global coordinator: the p62 protein. In addition, the implication in metastasis of another protein, FERMT2, suggests that both could constitute prognostic markers of the evolution of the disease.

Unlike other skin cancers, melanoma is one of the most aggressive tumors. It can lead to metastasis from the first moments, when it only has a thickness of millimeters. This metastasis also occurs in an apparently chaotic way, since many processes, which occur simultaneously but do not seem to be related to each other, are involved in it.

Now, scientists from the Melanoma Group of the National Center for Oncological Research (CNIO), in collaboration with the 12 de Octubre Hospital, have just found an order in this chaos. Their work shows that these metastatic processes do not occur as ‘independent mercenaries’; they are coordinated by a ‘general captain’: the p62 protein.

The study finds that one of these processes controlled by p62 is FERMT2, a protein that had not previously been linked to metastasis in melanoma, and shows that both FERMT2 and p62 could become a prognostic marker of disease progression in the patients. These important findings have been chosen for the January-2019 cover of the prestigious journal Cancer Cell.

It is very difficult to put order in the mechanisms that lead to melanoma and find what the bar code that defines this tumor is,” explains Marisol Soengas, head of the Melanoma Group. This is because the melanoma cells accumulate a very high number of alterations in the RNA. In addition, says Soengas, “there are more than 1,500 proteins that bind to RNA and the vast majority is unstudied.”

His group had found that one of the characteristics that distinguish melanoma from other tumors is the regulation of a self-cleansing cell process called autophagy. This is a system by which all the cells, also the tumor cells, eliminate components that they no longer need, and from which they extract energy to continue developing.

With this base, the researchers began to explore p62, a protein usually related to autophagy in tumor processes. “We were interested in p62 because it had been described as one of the yin and yang of cancer, for being able to favor or inhibit tumors according to the context,” says Panagiotis Karras, first author of the study.

Analyzing p62 levels in melanoma biopsies of patients, they observed that, the greater the melanoma progression, the higher the p62 levels. However, they found that in this tumor, p62 is not decisive in autophagy.

To find the main function of p62 in melanoma, the researchers carried out a complete omic study, which has used the most advanced bioinformatic technologies to obtain the first detailed characterization of p62 and all the processes in which it is involved in melanoma, including the study of the expression of the genes involved in these processes (transcriptomics), the structure and function of proteins (proteomics) and the interactions that occur between them (interactomics).

Metastasis of coordinated melanoma, not chaotic

Thanks to this comprehensive study, the researchers discovered a new and unexpected function of p62:  controlling the half-life of other proteins involved in melanoma metastasis.

Soengas continues: “By recruiting certain RNA-binding proteins, from among the 1,500 described, p62 controls multiple proteins that favor metastasis through processes apparently independent of each other, as survival, metabolism, cell cycle or invasion. Now we see that these processes are not independent, but have a common regulator.”

This work went further to find what other factors regulated by p62 could also affect the survival of patients. In this way, they identified a new protein, FERMT2, which was associated with a worse prognosis of metastatic melanomas.

For us, the pathologists, it was interesting to find that both p62 and FERMT2 are increased in samples of patients with melanoma metastasis, because so far we did not have good markers of tumor progression,” says José Luis Rodríguez-Peralto, head of Service of Pathological Anatomy of 12 de Octubre Hospital in Madrid, coauthor of this work.

In next steps of the investigation, the scientists will try to validate these results in a greater number of biopsies, as well as to deepen in the bar code of the melanoma, which separates it from other aggressive tumors.


Source: SINC